rs1057079

Positions:

• chr1-11145001-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004958.4(MTOR):​c.4731G>A​(p.Ala1577=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,390 control chromosomes in the GnomAD database, including 413,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (29032 hom., cov: 31)
  • Exomes 𝑓: 0.72 (384315 hom.)
• Consequence: MTOR NM_004958.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.869

Genes affected

MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]

MTOR-AS1 (HGNC:40242): (MTOR antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-11145001-C-T is Benign according to our data. Variant chr1-11145001-C-T is described in ClinVar as [Benign]. Clinvar id is 516654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11145001-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.869 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTOR	NM_004958.4	c.4731G>A	p.Ala1577=	synonymous_variant	33/58	ENST00000361445.9
MTOR-AS1	NR_046600.1	n.310+115C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTOR	ENST00000361445.9	c.4731G>A	p.Ala1577=	synonymous_variant	33/58	1	NM_004958.4	P1
MTOR-AS1	ENST00000445982.5	n.310+115C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85698 AN: 151880 Hom.: 29024 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.609

GnomAD3 exomes AF: 0.686 AC: 172411 AN: 251352 Hom.: 62071 AF XY: 0.692 AC XY: 93952 AN XY: 135848

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.813

Gnomad SAS exome AF: 0.654

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.718 AC: 1049597 AN: 1461392 Hom.: 384315 Cov.: 51 AF XY: 0.717 AC XY: 521497 AN XY: 727030

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.718

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.835

Gnomad4 SAS exome AF: 0.654

Gnomad4 FIN exome AF: 0.721

Gnomad4 NFE exome AF: 0.742

Gnomad4 OTH exome AF: 0.683

GnomAD4 genome AF: 0.564 AC: 85707 AN: 151998 Hom.: 29032 Cov.: 31 AF XY: 0.567 AC XY: 42106 AN XY: 74304

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.654

Gnomad4 ASJ AF: 0.593

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.640

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.611

Alfa AF: 0.689 Hom.: 63961

Bravo AF: 0.544

Asia WGS AF: 0.683 AC: 2376 AN: 3478

EpiCase AF: 0.732

EpiControl AF: 0.734

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.6
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057079; hg19: chr1-11205058; COSMIC: COSV63875443;